The antineoplastic drug cisplatin(cis-diaminedichloroplatinum (II) or “CDDP”), and related platinum based drugs including carboplatin and oxaliplatin, are widely used in the treatment of a variety of malignancies, including, but not limited to, cancers of the ovary, lung, colon, bladder, germ cell tumors and head and neck. Platinum analogs are reported to act, in part, by aquation to form reactive aqua species (Scheme 1), some of which may predominate intracellularly, and subsequently form DNA intrastrand adducts with purine bases (predominantly intrastrand adducts between adjacent purine bases and less commonly as interstrand crosslinks between purine bases) and disrupting the DNA structure and function, which is cytotoxic to cancer cells.

Cisplatin is relatively stable in human plasma, where a high concentration of chloride prevents aquation of cisplatin. Once cisplatin enters a tumor cell, where a much lower concentration of chloride exists, one or both of the chloride ligands of cisplatin is displaced by water to form a reactive aqua intermediate (as illustrated above), which in turn can react rapidly with DNA purines to form stable platinum-purine DNA adducts.
The postulated anti-tumor mechanisms of action of cisplatin-like agents is achieved by: (i) attacking the cellular DNA and forming intra- and inter-strand adducts; (ii) the N7 of Guanine (G) is the primary site of attack, followed by the N7 of Adenine (A); and (iii) the majority of adducts are of the intra-strand type with 60-70% being 1,2-GG intra-strand adducts, ˜30% being 1,2-AG intra-strand adducts, and ˜10% being 1,3-GG intra-strand adducts and ˜2% of 1,2-GG interstrand crosslinks.
As mentioned above, many cancers exhibit varying degrees of cytotoxic sensitivity to platinum drugs, as evidenced by tumor regression following initial treatment, but subsequently develop increasing levels of platinum resistance which is manifested as an absence of tumor shrinkage or by tumor growth progression or metastases during or following treatment with the platinum drug (i.e., “acquired resistance”).
An unwanted side reaction of platinum species is the reactions with physiological thiols and disulfides as well as proteins; such reactions are thought to be not beneficial in killing tumor cells because these reactions inactivate the platinum species thereby leading to platinum-resistant cancer cells.
Therefore, the development of platinum compounds that do not react as readily with physiological thiols/disulfides and proteins may be markedly more effective against platinum-resistant tumors than either cisplatin or the currently utilized compounds. New platinum agents are sought which can effectively kill tumor cells but that are also insensitive or less susceptible to tumor-mediated drug resistance mechanisms that are observed with other platinum agents.
In an attempt to solve this problem, we have been developing nitrile-based platinum derivatives which have shown better activity not only in the wild type cancer cells but also in cisplatin and oxaliplatin resistant cell lines. The structural formula for this analog is shown below:

In general, nitrile-ligand based platinum complexes are less polar and are more hydrophobic (i.e., water repelling) than the currently-marketed platinum-based drugs, and thus can be dissolved into less polar solvents including, but not limited to, methylene dichloride, dimethylacetamide (DMA), and the like. This greater lipophilicity may allow such analogs to be taken up more readily by cancer cells, by facile diffusion/transport through the lipid bilayer of the cell membrane, than current drugs, thereby increasing the available concentration of the platinum species that can participate in cytotoxic anti-tumor effects on the DNA within cancer cells.
Additionally, the lone pair of electrons on nitrogen in the nitrile group is located in the sp hybrid orbital, which is closer to the nitrogen nucleus than the sp3 hybrid orbital in the ammine ligand in cisplatin. Thus, in bis-nitrile-based platinum analogs, the attraction of the lone pair of electrons on nitrogen with platinum is greater than in the amine ligand and platinum in cisplatin. This effect results in decreasing the ionic effect between platinum(II) and the leaving group thereby increasing the covalent bonding between platinum and the leaving group. As a result, the leaving groups are more difficult to be displaced by substitution, including aquation, and therefore slower rates of aquation may be observed in nitrile-based platinum complexes as compared to ammine platinum complexes.
Slower rates of aquation is equally important from a pharmacological, toxicological, chemical and drug-resistance circumvention mechanistic points of view, by predicting the nitrile-containing platinum complexes described below to be less chemically reactive than cisplatin, carboplatin and oxaliplatin. Therefore, these nitrile-containing platinum complexes react more slowly with, and thereby avoiding unwanted platinum-sulfur and platinum-nitrogen conjugates with, the thiols, disulfides and proteins/peptides present in vivo; specifically the sulfur-containing physiological thiols, disulfides and peptides/amino acids, including but not limited to, glutathione, cysteine, homocysteine, methionine and all other sulfur-containing and imidazole-containing (e.g., histidine), or arginine or lysine di-tri- and larger peptides, that participate in tumor-mediated platinum drug resistance.
Therefore, these novel bis-nitrile-based platinum complexes have potential to circumvent de novo and acquired tumor-mediated cisplatin resistance and kill cancer cells with natural resistance to known platinum drugs. The platinum complexes described below are also thought to permit controlled reduction of the chemical reactivity of the platinum species to such a degree that greater amounts of the platinum species are also delivered intracellularly. This improved delivery of platinum that is available for intracellular DNA adducts formation is mediated by substantial reduction in the amount of non-effective and non-specific reactions of these novel platinum species with proteins and physiological thiols and disulfides, which can attenuate the antitumor effects of conventional platinum analogs.